Cellular expression, trafficking, and function of two isoforms of human ULBP5/RAET1G

Background: The activating immunoreceptor NKG2D is expressed on Natural Killer (NK) cells and subsets of T cells. NKG2D contributes to anti-tumour and anti-viral immune responses in vitro and in vivo. The ligands for NKG2D in humans are diverse proteins of the MIC and ULBP/RAET families that are upregulated on the surface of virally infected cells and tumours. Two splicing variants of ULBP5/RAET1G have been cloned previously, but not extensively characterised. Methodology/Principal Findings: We pursue a number of approaches to characterise the expression, trafficking, and function of the two isoforms of ULBP5/RAET1G. We show that both transcripts are frequently expressed in cell lines derived from epithelial cancers, and in primary breast cancers. The full-length transcript, RAET1G1, is predicted to encode a molecule with transmembrane and cytoplasmic domains that are unique amongst NKG2D ligands. Using specific anti-RAET1G1 antiserum to stain tissue microarrays we show that RAET1G1 expression is highly restricted in normal tissues. RAET1G1 was expressed at a low level in normal gastrointestinal epithelial cells in a similar pattern to MICA. Both RAET1G1 and MICA showed increased expression in the gut of patients with celiac disease. In contrast to healthy tissues the RAET1G1 antiserum stained a wide variety or different primary tumour sections. Both endogenously expressed and transfected RAET1G1 was mainly found inside the cell, with a minority of the protein reaching the cell surface. Conversely the truncated splicing variant of RAET1G2 was shown to encode a soluble molecule that could be secreted from cells. Secreted RAET1G2 was shown to downregulate NKG2D receptor expression on NK cells and hence may represent a novel tumour immune evasion strategy. Conclusions/Significance: We demonstrate that the expression patterns of ULBP5RAET1G are very similar to the well-characterised NKG2D ligand, MICA. However the two isoforms of ULBP5/RAET1G have very different cellular localisations that are likely to reflect unique functionality

What causes hidradenitis suppurativa? - 15 years after

The 14 authors of the first review article on hidradenitis suppurativa (HS) pathogenesis published 2008 in EXPERIMENTAL DERMATOLOGY cumulating from the 1st International Hidradenitis Suppurativa Research Symposium held March 30?April 2, 2006 in Dessau, Germany with 33 participants were prophetic when they wrote "Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy." (Kurzen et al. What causes hidradenitis suppurativa? Exp Dermatol 2008;17:455). Fifteen years later, there is no doubt that the desired renaissance of solid basic HS research is progressing with rapid steps and that HS has developed deep roots among inflammatory diseases in Dermatology and beyond, recognized as ?the only inflammatory skin disease than can be healed?. This anniversary article of 43 research-performing authors from all around the globe in the official journal of the European Hidradenitis Suppurativa Foundation e.V. (EHSF e.V.) and the Hidradenitis Suppurativa Foundation, Inc (HSF USA) summarizes the evidence of the intense HS clinical and experimental research during the last 15 years in all aspects of the disease and provides information of the developments to come in the near future

What causes hidradenitis suppurativa ?—15 years after

The 14 authors of the first review article on hidradenitis suppurativa (HS) pathogenesis published 2008 in EXPERIMENTAL DERMATOLOGY cumulating from the 1st International Hidradenitis Suppurativa Research Symposium held March 30–April 2, 2006 in Dessau, Germany with 33 participants were prophetic when they wrote “Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy.” (Kurzen et al. What causes hidradenitis suppurativa? Exp Dermatol 2008;17:455). Fifteen years later, th

Rôle de l'interaction MICA-NKG2D dans l'immunité innée et adaptative (exemples du thymone et de la maladie coeliaque)

Les molécules MIC sont des ligands du récepteur activateur NKG2D exprimé sur les lymphocytes T CD8+ et NK. Nous avons étudié le rôle de l'interaction MICA/NKG2D dans la maturation du répertoire T dans le thymus et dans la destruction de l'épithélium intestinal par les lymphocytes intra-épithéliaux dans la maladie coeliaque. l'acquisition de NKG2D dans le thymus T CD8+ les plus matures prêts à émigrer en périphérie. Les corpuscules de Hassal expriment MIC dans le thymus normal. L'hyperexpression de MIC au cours du thymone s'accompagne d'une diminution du pourcentage des cellules NKG2D+ qui présentent un phénotype moins mature. L' expression de MIC est très augmentéeà la surface des cellules épithéliales intestinales des patients avec une maladie coeliaque active et est induite in vitro par la gliadine...PARIS5-BU-Necker : Fermée (751152101) / SudocSudocFranceF

Microbiome of HIV-infected people

International audienceConsistent interactions between the gut microbiome and adaptive immunity recently led several research groups to evaluate modifications of human gut microbiota composition during HIV infection. Herein we propose to review the shifts reported in infected individuals, as their correlation to disease progression. Though the gut microbiota is consistently altered in HIV individuals, the literature reveals several discrepancies, such as changes in microbial diversity associated with HIV status, taxa modified in infected subjects or influence of ART on gut flora restoration. Similarly, mechanisms involved in interactions between gut bacteria and immunity are to date poorly elucidated, emphasizing the importance of understanding how microbes can promote HIV replication. Further research is needed to propose adjuvant therapeutics dedicated to controlling disease progression through gut microbiome restoration

Expression of major histocompatibility complex class I chain-related molecule A, NKG2D, and transforming growth factor-beta in the liver of humans with alveolar echinococcosis: new actors in the tolerance to parasites?

International audienceBACKGROUND: Echinococcus multilocularis growth and persistent granuloma, which lead to the development of the severe parasitic disease alveolar echinococcosis (AE), might be caused by abnormal expression of stress-induced proteins, with subsequent abnormalities in T cell activation. Similar to its involvement in tumors, the NKG2D-major histocompatability complex class I chain-related molecules A and B (MICA/B) signaling system could be involved in host-parasite interactions; however, its involvement in helminthic diseases has never been studied. METHODS: We studied MICA/B, NKG2D, and transforming growth factor-beta (TGF-beta) expression on liver sections and measured levels of soluble MICA in serum samples obtained from patients with progressive AE. Livers from healthy and cirrhotic subjects were studied as controls. RESULTS: Expression of MICA/B proteins was strongly enhanced in the hepatocytes and endothelial and bile duct cells; in the CD68+ cells of the periparasitic infiltrate, especially epithelioid and giant cells; and, also, in the metacestode germinal layer. Strong expression of MICA/B in the liver contrasted with low numbers of NK cells and lack of expression of NKG2D on the numerous CD8+ T lymphocytes of the periparasitic infiltrate, as well as with the absence of soluble MICA in serum. TGF-beta was strongly expressed by most of the infiltrating lymphocytes. CONCLUSIONS: Sustained expression of MICA/B molecules and TGF-beta might lead to modulation of NKG2D with subsequent inhibition of NKG2D-dependent cytotoxicity. Abnormalities of this signaling system could contribute to parasitic evasion of the host's immunity

Clinical association of mixed connective tissue disease and ă granulomatosis with polyangiitis: a case report and systematic screening ă of anti-U1RNP and anti-PR3 auto-antibody double positivity in ten ă European hospitals

International audienceWe report here the case of a 50-years-old man treated for mixed ă connective tissue disease (MCTD) positive for anti-U1 ribonucleoprotein ă (U1RNP) antibodies who secondarily developed a granulomatosis with ă polyangiitis (GPA) associated with anti-proteinase 3 anti-neutrophil ă cytoplasmic antibodies (PR3-ANCA). We then evaluated the frequency of ă the association between anti-U1RNP and anti-PR3-ANCA antibodies by a ă systematic retrospective study in ten European hospitals. Overall, out ă of 11,921 samples analyzed for both auto-antibodies, 18 cases of ă anti-U1RNP and anti-PR3-ANCA double positivity were found and only one ă patient presented with both MCTD and GPA symptoms. Our retrospective ă analysis indicates that anti-U1RNP and anti-PR3-ANCA antibodies double ă positivity is infrequent and very rarely associated with both MTCD and ă GPA. Our observation describes for the first time the coexistence of ă MTCD and severe GPA in a Caucasian patient. Association of anti-U1RNP ă and ANCA antibodies was rarely reported in the literature. Eleven cases ă of MCTD and ANCA vasculitis have been reported to date, with only two ă cases with anti-PR3-ANCA association, and only one vasculitis. The seven ă other cases reported in the literature presented with an association of ă MCTD and microscopic polyangiitis which appears to be a more frequent ă presentation than MTCD associated with GPA

Solid phase assays versus automated indirect immunofluorescence for detection of antinuclear antibodies

Solid phase assays (SPAs) and automated microscope systems are increasingly used to screen for antinuclear antibodies (ANAs). The goal of this study was to evaluate the performance of three automated ANA screening assays; NOVA Lite HEp-2 using NOVA View® (NV, Inova Diagnostics), an automated indirect immunofluorescence method, EliA™ CTD Screen (Fluorescence Enzyme Immunoassay, FEIA; Thermo Fisher) and QUANTA Flash® CTD Screen Plus (Chemiluminescence immunoassay, CIA; Inova Diagnostics). The assays were performed on 480 diagnostic samples from patients with an ANA-associated rheumatic disease (AARD; systemic lupus erythematosus, primary Sjögren's syndrome, systemic sclerosis, inflammatory myopathy, mixed connective tissue disease) and on 767 samples from diseased and healthy controls. Using cut-offs proposed by the manufacturers, the sensitivity was 95%, 80.5% and 86% for NV, FEIA and CIA, respectively. The corresponding specificity was 61% (NV), 97.5% (FEIA) and 88% (CIA). The sensitivity associated with a specificity of ~95% was 79%, 82% and 78% for NV, FEIA, and CIA, respectively. Receiver operating characteristics (ROC) curve analysis revealed no differences in area under the curve (AUC) between the 3 assays when all diseases were grouped. For Sjögren's syndrome, the AUC was higher for SPAs than for NV, whereas for systemic sclerosis, the AUC was higher for NV than for CIA. For all assays, the likelihood ratio for AARD increased with increasing antibody levels and for double positivity of NV with SPA. In conclusion, the performance of automated SPA and IIF was assay- and disease-dependent. Taking into account antibody levels and combining IIF with SPA adds value.status: accepte

HIV-1 treatment timing shapes the human intestinal memory B-cell repertoire to commensal bacteria

International audienceAbstract HIV-1 infection causes severe alterations of gut mucosa, microbiota and immune system, which can be curbed by early antiretroviral therapy. Here, we investigate how treatment timing affects intestinal memory B-cell and plasmablast repertoires of HIV-1-infected humans. We show that only class-switched memory B cells markedly differ between subjects treated during the acute and chronic phases of infection. Intestinal memory B-cell monoclonal antibodies show more prevalent polyreactive and commensal bacteria-reactive clones in late- compared to early-treated individuals. Mirroring this, serum IgA polyreactivity and commensal-reactivity are strongly increased in late-treated individuals and correlate with intestinal permeability and systemic inflammatory markers. Polyreactive blood IgA memory B cells, many of which egressed from the gut, are also substantially enriched in late-treated individuals. Our data establish gut and systemic B-cell polyreactivity to commensal bacteria as hallmarks of chronic HIV-1 infection and suggest that initiating treatment early may limit intestinal B-cell abnormalities compromising HIV-1 humoral response